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COPYRIGHT © 2002 BY THE JOURNAL OF BONE AND JOINT SURGERY, INCORPORATED

Granulomatous Inflammation
After Hylan G-F 20
Viscosupplementation of the Knee
A REPORT OF SIX CASES
BY ANDREW L. CHEN, MD, MS, PANNA DESAI, MD, EDWARD M. ADLER, MD, AND PAUL E. DI CESARE, MD
Investigation performed at the New York University-Hospital for Joint Diseases, New York, NY

Background: Recently, intra-articular viscosupplementation with hyaluronate-derived products has gained popu-
larity as a palliative modality for the treatment of osteoarthritis of the knee. Mild pain or swelling at the site of
injection may occur in up to 20% of patients, although severe local inflammation, warmth, and joint effusion are
rare. We present a series of six cases in which granulomatous inflammation of the synovium was observed af-
ter hyaluronate viscosupplementation of the knee.
Methods: Six knees (five patients) treated with intra-articular Hylan G-F 20 viscosupplementation underwent a
surgical procedure because of persistent symptoms. Routine histopathological evaluation, supplemented by
alcian-blue staining and hyaluronidase digestion, was performed in each case.
Results: Chronically inflamed synovium with areas of histiocytic and foreign-body giant-cell reaction was ob-
served surrounding acellular, amorphous material. The material stained with alcian blue, a stain for hyalur-
onate, which disappeared after hyaluronidase digestion.
Conclusions: We believe that the injected hyaluronate (Hylan G-F 20) may have been responsible for the syno-
vitis in our patients and thus may be a pathological cause of recalcitrant symptoms after such injection. It is not
known whether the responsible pathological agent was the hyaluronate derivative, a contaminant of the purifica-
tion process, or a component of the carrier substance. Importantly, it appears that the findings in these pa-
tients most likely represent a previously unreported pathological response to a viscosupplementation product.
This report should raise clinical awareness about this potential complication.

O
steoarthritis of the knee is a common source of disabil-
ity in the aging population. Traditional nonoperative
treatment options include activity modification, weight
loss, exercise, assistive devices for walking, nonsteroidal anti-
inflammatory drugs, analgesics, and corticosteroid injections.
Medical management is effective for many patients without ad-
vanced disease, but nonsteroidal anti-inflammatory drugs may
have major untoward effects. The economic burden of acute
gastritis associated with such drugs has been estimated to ex-
ceed $500 million annually1.
In recent years, intra-articular viscosupplementation
with hyaluronate-derived products has gained popularity as a
palliative modality for the treatment of osteoarthritis of the
knee. Although numerous clinical trials2-16 have documented
the safety of such procedures, concerns remain regarding their
efficacy and cost2,6,13,14. The most common adverse reaction is
mild pain or swelling at the site of the injection, which may
occur in up to 20% of patients17-19. Severe local inflammation,
warmth, and joint effusion are rare, and no systemic compli-
cations have been reported, to our knowledge.
We are not aware of any studies in which synovium was
subjected to histopathological analysis after hylan viscosup-
plementation in humans. We present six cases in which syn-
ovial granulomatous inflammation was observed following
intra-articular viscosupplementation of the knee.
Materials and Methods
ix knees (five patients) that received a series of three intra-
S articular injections of Hylan G-F 20 viscosupplementation
(Synvisc; distributed by Wyeth-Aherst Pharmaceuticals, Phila-
delphia, Pennsylvania, and manufactured by Biomatrix,
Ridgefield, New Jersey) underwent a surgical procedure be-
cause of persistent symptoms. In each case, granulomatous in-
flammation observed on routine histopathological evaluation
prompted a review of the patient’s history as well as further
characterization of the etiology of the inflammation.
There were three women and two men with an average
age of fifty-five years (range, thirty-seven to seventy-two
years). All patients had a primary diagnosis of osteoarthritis,
which primarily involved the patellofemoral articulation in
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one knee, primarily involved the medial knee compartment in
three, and was tricompartmental in two.
No patient had a history or ongoing evidence of in-
fection, evidence of immunocompromise, or a history of
long-term use of immunosuppressive medications (e.g.,
chemotherapeutic agents or oral corticosteroids). No pa-
tient had an allergy to chicken or egg products. Two pa-
tients had received prior injections of corticosteroids to the
knee. Previous surgical procedures on the knee included
open reduction and internal fixation of a patellar fracture
in one patient and arthroscopic débridement in two. Rou-
tine histological examination of arthroscopic shavings
from the latter procedures revealed no abnormalities.
Each patient had pain, swelling, and warmth in the knee
following viscosupplementation. The swelling and warmth
developed within forty-eight hours after the injection, peaked
at four to five days, and gradually resolved in approximately
one to two weeks following the final injection. In two knees
the pain was unchanged compared with that prior to injec-
tion, and in four knees the pain was worse than that prior to
injection. The increase in pain coincided with the onset of
swelling and warmth, but it persisted following resolution of
both the warmth and the swelling. No patient had a fever after
the injection, and no knee was erythematous. All patients
were managed symptomatically with nonsteroidal anti-
inflammatory medications, but relief was minimal. No patient
had evidence of peripheral leukocytosis on routine preopera-
tive evaluation, and all had a normal C-reactive protein level.
The average erythrocyte sedimentation rate was 19 mm/hr
(range, 10 to 24 mm/hr). Knee aspiration was performed in
four knees to evaluate the possibility of joint infection. In no
case was frank purulence or a cloudy aspirate encountered,
and no organisms were seen on Gram staining. All four aspi-
rates demonstrated a white blood-cell count of <10,000/mm3
(<10.0 × 109/L) and fewer than five neutrophils per high-
G R A N U L O M A T O U S I N F L A M M A T I O N A F T E R H Y L A N G-F 20
VI S CO S U P P L E M E N T A T I O N O F T H E KN E E
power field; cultures of the aspirated material were negative.
Two knees underwent arthroscopic débridement at an av-
erage of four months (two and six months) after the last injec-
tion of Hylan G-F 20. Specimens were collected with use of a
specimen trap connected to the arthroscopic shaver by suction
tubing and were preserved in 10% buffered formalin. Four
knees underwent total knee arthroplasty at an average of seven
months (range, five to nine months) after viscosupplementa-
tion. As is customary at this institution, all intraoperative tissue
specimens were submitted for routine histological examination.
Results
Gross Pathology
he arthroscopic specimens consisted of multiple irregular
T fragments of soft gray-tan tissue admixed with cartilage
fragments. The specimens obtained during the total knee re-
placements consisted of tibial plateau, femoral condyle, shaved
bone fragments, meniscus, and capsular tissue. The bone frag-
ments demonstrated focal loss of articular cartilage with ebur-
nation and sclerosis of underlying bone as well as peripheral
osteophytes. Fibrillation of the meniscal tissue was evident. Fo-
cal areas of proliferative synovial hypertrophy were present.
Light Microscopy
All sections were stained with hematoxylin and eosin. In addi-
tion, soft-tissue sections from each knee were stained with alcian
blue, with and without hyaluronidase digestion, as well as with
special stains for microorganisms (acid-fast, periodic acid-Schiff,
and Gram stains). Soft-tissue sections from each case revealed
similar histological findings. Chronically inflamed synovium
(hallmarked by the presence of lymphocytes and monocytes)
and adipose tissue containing numerous areas of histiocytic and
foreign-body giant-cell reaction surrounding acellular, amor-
phous, pink fluid-like material were noted (Fig. 1). Use of the
special stains for microorganisms revealed negative findings. No
Fig. 1
Synovial tissue containing palisad-
ing granulomas with prominent
histiocytic and giant-cell cuffing
surrounding the acellular, pink
fluid-like foreign material. Chroni-
cally inflamed synovium is present
in the lower left corner (hematoxy-
lin and eosin, ×16).
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birefringent crystalline material was observed under polarized
light microscopy. The acellular material stained with alcian
blue (Fig. 2), a stain for hyaluronate, which disappeared after
hyaluronidase digestion (Fig. 3). This result is diagnostic for hy-
aluronate material20. None of the bone fragments revealed gran-
ulomatous inflammation.
Two patients underwent arthroscopic débridement of
the contralateral knee, which had not been treated with Hylan
G-F 20 viscosupplementation. Granulomatous inflammation
was not observed in either of these knees.
Discussion
yaluronate is critical for normal joint homeostasis. It
H contributes to the viscoelasticity of synovial fluid as well
G R A N U L O M A T O U S I N F L A M M A T I O N A F T E R H Y L A N G-F 20
VI S CO S U P P L E M E N T A T I O N O F T H E KN E E
Fig. 2
The acellular material dem-
onstrated positive staining
reaction to alcian blue,
which suggested that it
was hyaluronan (×40).
as to joint lubrication and mechanical buffering of load
transmission21,22. Physiologically, hyaluronate may result in its
own upregulation, and it may impart anti-inflammatory and
antinociceptive properties to synovial fluid21.
In osteoarthritis, the concentration of hyaluronate in
synovial fluid diminishes to one-half to one-third of its normal
value, with a concomitant reduction in the molecular weight
(normal, 4 to 5 × 106 Da) and intermolecular interaction23. Ac-
cordingly, lower dynamic viscoelasticity of and lubrication by
the synovial fluid result in increased stresses across the articular
surface, while altered barrier and filter integrity influences nu-
trient provision and waste removal from articular cartilage. In
an attempt to reproduce the rheological, anti-inflammatory, an-
abolic, analgesic, and chondroprotective properties of normal
Fig. 3
Alcian-blue staining attributable to
hyaluronic acid was selectively elimi-
nated by hyaluronidase digestion,
confirming the substance to be
hyaluronan (×16).
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synovial fluid, intra-articular viscosupplementation with exoge-
nously derived hyaluronate derivatives was proposed2,6,8,12,24.
Suitability of a substance for use as a viscosupplement is
determined by a lack of immunogenicity, permeability to pas-
sive diffusion within synovial fluid, prolonged half-life within
synovium, and restoration of rheological properties of syno-
vial fluid23,24. Various preparations of hyaluronate derivatives
of varying molecular weight, concentration, and degree of
cross-linking have been introduced, although only three—Hy-
algan (Sanofi Pharmaceuticals, New York, NY), Supartz (Seika-
gaku, Falmouth, Massachusetts), and Hylan G-F 20 (Synvisc;
Wyeth-Aherst/Biomatrix)—are commercially available in the
United States. With the exception of one product (Neovisc;
Stellar International, London, Ontario, Canada) that is pro-
duced in vitro from bacterial culture, the hyaluronate for
viscosupplements is isolated from rooster combs by a process
that separates the noninflammatory hyaluronate component.
Hylans are produced by covalent cross-linking of individual
hyaluronate molecules to produce polymers that have theo-
retically increased viscoelasticity, superior lubrication, and
increased resistance to degradation compared with non-cross-
linked products25.
Histological analyses of specimens from joints treated
with hyaluronate viscosupplementation in animal models
have yielded conflicting results. Armstrong et al.26 demon-
strated, in an ovine model, that the administration of hyal-
uronate viscosupplementation begun sixteen weeks after
meniscectomy resulted in less histological evidence of articu-
lar and subchondral damage at necropsy five weeks later than
did injection of saline solution. Schiavinato et al.27 reported
that hyaluronate injections begun on the second week after
sectioning of the anterior cruciate ligament in Pond-Nuki
dogs resulted in relative preservation of the articular cartilage
at seven weeks as well as direct inhibition of the development
of a fibroblast-like cell layer that was seen in the untreated
joints. Furthermore, it was postulated that hyaluronate may
limit the synovial inflammatory response to osteoarthritic
changes within the joint27. Conversely, in a canine model in
which hyaluronate injections were begun one day after sec-
tioning of the anterior cruciate ligament, Smith et al.28 found
no significant changes in synovial fluid volume or hyaluronate
molecular weight in the synovial fluid at twelve weeks after the
surgery. Furthermore, they found that hyaluronate injections
did not restore the hyaluronate concentration of the synovial
fluid to that found in normal canines (not treated with an op-
eration). In another report, the same authors observed that
hyaluronate viscosupplementation in a canine osteoarthritis
model did not alter the development of osteophytes or articu-
lar fibrillation and may actually have resulted in lower pros-
taglandin concentrations29. To our knowledge, however, no
human or animal studies have previously demonstrated syn-
ovial granulomatous inflammation to be a potential compli-
cation of hyaluronate viscosupplementation.
The overall incidence of adverse reactions after hyal-
uronate viscosupplementation has been reported to be 1% per
injection17, with the majority consisting of localized inflam-
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mation at the site of injection. Puttick et al.18 observed a “clini-
cally significant” local inflammatory reaction after 11% of
injections (in 27% of patients). However, in a large series in
which 1537 injections were administered, Lussier et al.7 ob-
served a local reaction after only 2.7% (in 8.3% of patients),
and 79% of the reactions resolved without long-term sequelae.
Five patients had a total of nine reactions with long-term re-
sidual swelling and pain7. Adams et al.22 summarized the ex-
perience with various hyaluronate viscosupplementation
preparations, reporting an overall incidence of adverse events
of 2% to 4%; almost all were local inflammatory reactions,
with no adverse sequelae. The authors recognized infection to
be a potentially disastrous complication, although no infec-
tion had been directly attributed to product contamination22.
Synovial granulomatous inflammation is a well-recog-
nized consequence of the generation of particulate debris after
total joint arthroplasty, and it occurs in response to metal30,
polyethylene30-32, and polymethylmethacrylate cement de-
bris32,33. It may also arise as a consequence of mycobacterial
joint infection or bursitis. The common underlying mecha-
nism of granuloma formation is the inability of the host im-
mune system to effectively digest or degrade the foreign
material. The essential feature consists of a macrophage-
mediated foreign-body reaction in which release of inflamma-
tory mediators results in recruitment of cells of the monocyte
lineage with subsequent multinucleated giant-cell formation.
Coalescence of giant cells around undegradable matter results
in granuloma formation.
In our patients, the granulomatous inflammation appears
to have been caused by the injected viscosupplementation ma-
terial. Histological analysis demonstrated foreign-body granu-
lomatous inflammation surrounding acellular material in a
palisading fashion in all cases. The differential diagnosis for
these palisading granulomas included infectious granuloma,
crystal-induced reaction (gout), and foreign-body reaction to
the previously injected viscosupplement (hyaluronate). Use of
special stains for microorganisms revealed negative findings.
The material was not birefringent under polarized light micros-
copy, which excluded the diagnosis of crystal-induced granu-
loma. Although there are no specific immunohistochemical
stains for Hylan G-F 20, positive staining with alcian blue (in-
dicative of the presence of hyaluronate) strongly suggested that
Hylan G-F 20 was the material within the granulomas. Our re-
sults suggest that the highly cross-linked, high-molecular-
weight hyaluronate derivative was most likely responsible for
the granulomatous inflammation; however, the possibility of
contaminants within the viscosupplement injectant cannot be
excluded. The fact that two patients who had had surgery, but
not an injection, in the contralateral knee showed no granulo-
matous reaction in that knee eliminates the possibility of some
other systemic etiology for these pathological findings. The al-
cian blue-positive staining of the observed material and the fact
that it resolved after hyaluronidase digestion in each of our cases
provide persuasive evidence that the hyaluronate derivative
used for viscosupplementation was responsible for the observed
granulomatous inflammation and may be a pathological cause
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of recalcitrant symptoms after such injections.
To our knowledge, no report has specifically associated
the use of hyaluronate-derived viscosupplementation prod-
ucts with histopathological evidence of adverse effects. As
viscosupplements are considered medical devices rather than
pharmaceutical agents by the United States Food and Drug
Administration (and the equivalent agency in Canada), they
are not subjected to the phased, stringent review process re-
quired for drug approval23,34. We presented six cases in which
granulomatous inflammation of the synovium may have
contributed to unremitting knee symptoms, necessitating
additional evaluation and surgical intervention. Because
histopathological analysis of the synovium is not routinely
performed after viscosupplementation, the incidence of
granuloma formation after such injections is unknown.
Moreover, it is not known whether the pathological agent re-
sponsible is the hyaluronate derivative, a contaminant of the
purification process, or a component of the carrier sub-
stance. Importantly, it appears that the synovial granuloma-
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Andrew L. Chen, MD, MS
Panna Desai, MD
Edward M. Adler, MD
Paul E. Di Cesare, MD
Departments of Orthopaedic Surgery (A.L.C., E.M.A., and P.E.D.C.) and
Pathology (P.D.), New York University-Hospital for Joint Diseases, 301
East 17th Street, New York, NY 10003. E-mail address for P.E. Di Cesare:
pedicesare@aol.com
The authors did not receive grants or outside funding in support of their
research or preparation of this manuscript. They did not receive pay-
ments or other benefits or a commitment or agreement to provide such
benefits from a commercial entity. No commercial entity paid or
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